Source-Dependent Functions for TNF

Grivennikov et al. created transgenic mice with tumor necrosis factor (TNF) selectively deleted in specific leukocyte types to investigate differences in TNF function that depend on the cellular source. TNF, a cytokine that has been implicated in cell trafficking, inflammatory responses, and defense against pathogens, has both beneficial and deleterious effects. Thus, whereas inhibition of TNF activity may be beneficial in various inflammatory disorders, such inhibition may increase susceptibility to certain pathogens. Grivennikov et al. found that mice that did not express TNF in macrophages or neutrophils (MN-TNF KO mice) had reduced serum concentrations of TNF compared with those of wild-type mice after injection of lipopolysaccharide (LPS, which elicits TNF production through Toll-like receptor signaling). However, mice lacking T cell (T-TNF KO) or B cell (B-TNF KO) TNF did not. MN-TNF KO mice were resistant to septic shock produced by injection of LPS plus D-galactosamine, whereas T-TNF KO and B-TNF KO mice were not. When toxic shock was induced by superantigen from Staphylococcus aureus, however, T-TNF KO and MN-TNF KO mice were both resistant, whereas B-TNF KO mice were not. Macrophage- and neutrophil-derived TNF was required for resistance to infection with the intracellular bacterium Listeria monocytogenes, whereas B cell-derived TNF was dispensable and T cell-derived TNF was protective only under conditions of high bacterial load. Loss of either T cell-derived TNF or of macrophage- and neutrophil-derived TNF was protective in a mouse model of autoimmune hepatitis. Thus, the authors conclude that TNF derived from different sources plays distinct biological roles and suggest that selective inhibition of T cell-derived TNF production may be therapeutically preferable to systemic inhibition of TNF activity.